Providing Support to Sarcoidosis and Lyme Disease Communities. A group of ladies got together in August 2011 to discuss their journey and experiences with Sarcoidosis and one who possibly has Lyme Disease. As a result Sue Sherratt decided to develop a web site for Sarcoidosis and Lyme Disease Support in Australia. This blog is a result of that meeting. You can reach Sarcoidosis Australia by emailing support@sarcoidosisaustralia.com.

Tuesday, 29 November 2011

Abstract

Background: Sarcoidosis affects the central nervous system more frequently than previously appreciated. The diagnosis of neurosarcoidosis is often delayed, potentially leading to serious complications. Symptoms, when present, are not specific, may be subtle and resemble those of other neurologic diseases.

Review Summary: During the past decade, significant progress has been made in understanding the epidemiology and pathophysiology of neurosarcoidosis, as well as the ability to diagnose and treat this disease. Studies have shown that the optimal diagnostic imaging modality for neurosarcoidosis is magnetic resonance imaging with gadolinium as it enhances visualization of granulomatous infiltration in neural tissue. Subclinical neurosarcoidosis may not be uncommon in patients with sarcoidosis. It is now evident that neurosarcoidosis does not invariably present as a catastrophic event. Adverse effects associated with high-dose systemic corticosteroids, the standard therapy, have discouraged practitioners from initiating treatment in the absence of significant symptomatic neurologic disease. However, other immunosuppressive agents as well newer biologic agents have emerged as an effective, well-tolerated therapeutic alternative to corticosteroids, which are often effective in corticosteroid-recalcitrant cases.

Conclusion: Neurologists should be aware of the varying presentations of neurosarcoidosis since early recognition of neurologic involvement in patients with undiagnosed or proven sarcoidosis is currently possible and critical to the prevention of disabling complications.

What is sarcoidosis?

Sarcoidosis is an inflammatory disease that affects one or more organs but most commonly affects the lungs and lymph glands. As a result of the inflammation, abnormal lumps or nodules (called granulomas) form in one or more organs of the body. These granulomas may change the normal structure and possibly the function of the affected organ(s).

What causes sarcoidosis?

The exact cause of sarcoidosis is not known. The disease can appear suddenly and then disappear, or it can develop gradually and produce symptoms that come and go for a lifetime.

Researchers believe that the disease is caused by an abnormal immune response. (The body’s defense system does not react as it should to a foreign substance "intruder.") In a healthy person, inflammation occurs as the cells of the body’s immune system come together to fight the intruder at an organ or tissue site. In a person with sarcoidosis, however, cells that come to fight end up clumping together into small lumps called granulomas.

It’s still uncertain which foreign substance "triggers" the body’s abnormal response. Some researchers suggest that fungi, viruses, or bacteria are likely triggers. In fact, cases of sarcoidosis have occurred in groups of people who had close contact with each other, as well as in recipients of heart, lung and bone marrow transplants. But, so far, no data have been able to convincingly and consistently establish this "infectious" connection as the cause of the disease. However, some types of bacteria have recently emerged as possible candidates and continue to be closely studied.

Does sarcoidosis run in families?

While the latest research does appear to indicate a genetic susceptibility to the disease, more research is needed to clearly identify and confirm the genes involved. However, numerous reports have revealed racial/ethnic and family-line occurrences, including the following:

Irish immigrants in London have a three-fold likelihood of developing sarcoidosis compared with native Londoners.

Natives of Martinique living in France have an eight-fold higher chance of developing the disease compared with the native French population.

African-Americans face a 4 to 17 times greater risk of the disease compared with Caucasians.

Within individual families, the presence of the disease in a first- or second-degree relative increases the risk by nearly five-fold.

Still other types of disease clusters have been identified, including seasonal and occupational clustering. Researchers in Greece, Spain, and Japan have reported a clustering of diagnoses of sarcoidosis in the months of March to May, April to June, and June to July. In the United States, a higher percentage of cases of sarcoidosis have been reported in health care workers, naval aircraft servicemen, and firefighters.

What are the symptoms of sarcoidosis?

The symptoms of sarcoidosis can vary greatly from individual to individual, and depend on which tissues and organs are affected. In some people, symptoms may begin suddenly and/or severely and subside in a short period of time. Others may have no outward symptoms at all, even though organs are affected. Still others may have symptoms that appear slowly and subtly, but last or recur over a long time span.

Most common initial symptoms:

Shortness of breath (dyspnea)

Cough that won’t go away

Reddish bumps or patches on the skin or under the skin

Enlarged lymph glands in the chest and around the lungs that produces cough and shortness of breath

How does the condition progress?

Although no one can predict how sarcoidosis will progress in an individual patient, some clues as to disease course can be gained from patient symptoms, findings from physical and laboratory studies, and patient race. For example, a sudden onset of general symptoms--such as weight loss, fatigue, fever, or just an overall feeling of ill health--usually means that the course of sarcoidosis will be relatively short and mild in severity. Symptoms of shortness of breath and some types of skin involvement mean that sarcoidosis will be more long-lasting and severe.

In Caucasians, the disease often appears suddenly, which usually indicates a more mild form of the disease that is of short duration. African-Americans and Puerto Ricans, on the other hand, tend to develop the more long-term and severe form of the disease.

In the United States, the lungs are often the most common site of initial symptoms for those who experience a gradual onset of their long-term disease. Lung symptoms are common in African-Americans, Puerto Ricans, and Scandinavians. Persistent dry cough, fatigue, and shortness of breath are the most common initial lung-related complaints.

Some patients who experience sudden onset of disease have Lofgren’s syndrome, a form of sarcoidosis that affects the lymph nodes and is accompanied by a skin condition that produces red nodules under the skin, as well as fever and arthritis pain. Patients with Lofgren’s syndrome usually can expect a good outcome; the disease goes away on its own in 85% to 90% of people.

How sarcoidosis progresses: What happens at the tissue level

At the tissue or cellular level, sarcoidosis disease progression can be divided into three phases:

The first change that is seen is inflammation.

In the second phase, granulomas form. Granulomas are masses or nodules of chronically inflamed tissue and are the classic sign of sarcoidosis Granulomas are the body’s attempt to wall off or isolate organisms and other foreign particles that are difficult for the immune system to eradicate or dispose of.

In the third phase, fibrosis (scarring) of tissues or organs occurs. If scarring is extensive in a vital organ, sarcoidosis is sometimes fatal.

In some people, the disease advances from one phase to the next in the tissues of the organ affected. In others, the different phases of tissue changes take place within the same organ at the same time. In many patients with sarcoidosis, the granulomas go away on their own in 2 to 3 years without the patient knowing or doing anything about them. In others, the granulomas progress to irreversible fibrosis. The immune system changes that allow one person’s disease to progress while another person’s disease resolves are not well understood and continue to be investigated.

How is sarcoidosis diagnosed?

Because the symptoms and laboratory findings associated with sarcoidosis can occur in other diseases, there is no single test that can diagnose it. However, the classic sign of the disease is the formation of granulomas (abnormal masses or nodules consisting of inflamed tissue) in one or more of the major organs of the body. Sarcoidosis-related granulomas are not different from granulomas that occur in other diseases. As a result, a complete physical exam and medical history--including occupational history, medication history, and environmental exposures--must be made before concluding that the illness is, in fact, sarcoidosis.

How is sarcoidosis treated?

There is no cure for sarcoidosis, but the disease may get better on its own over time. Many people with sarcoidosis have mild symptoms and do not require any treatment at all. Treatment, when it is needed, generally falls into two categories: maintenance of good health practices and drug treatment. Good health practices include:

Getting regular check-ups with your health care provider

Eating a well-balanced diet with a variety of fresh fruits and vegetables

Avoiding excessive amounts of calcium-rich foods (such as dairy products, oranges, and canned salmon with bones), vitamin D, and sunlight. Daily sunbathing is an example of excessive sunlight and should be avoided; sunlight received from activities of everyday living is acceptable. (The advice in this bullet point is limited to patients with high blood or urine levels of calcium.)

Drug treatments are used to relieve symptoms, reduce the inflammation of the affected tissues, reduce the impact of granuloma development, and prevent the development of lung fibrosis and other irreversible organ damage.

Corticosteroids are particularly effective in reducing inflammation, and are typically the first drugs used in treating sarcoidosis. The oral corticosteroid prednisone is the most commonly used corticosteroid. For patients who cannot take prednisone or for whom a longer course of treatment is necessary, there are other anti-inflammatory medications that can be used.

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This information is provided by the Cleveland Clinic and is not intended to replace the medical advice of your doctor or health care provider. Please consult your health care provider for advice about a specific medical condition. This document was last reviewed on: 2/28/2011...#11863

Abstract

Introduction

Lyme neuroborreliosis is the most common bacterial central nervous system infection in the temperate parts of the northern hemisphere. Even though human immunodeficiency virus (HIV) -1 infection is common in Lyme borreliosis endemic areas, only five cases of co-infection have previously been published. Four of these cases presented with typical Lyme neuroborreliosis symptoms such as meningoradiculitis and facial palsy, while a fifth case had more severe symptoms of encephalomyelitis. All five were treated with intravenous cephalosporins and clinical outcome was good for all but the fifth case

Case presentations

We present four patients with concomitant presence of HIV-1 infection and Lyme neuroborreliosis diagnosed in Western Sweden. Patient 1 was a 60-year-old Caucasian man with radicular pain and cognitive impairment. Patient 2 was a 39-year-old Caucasian man with headaches, leg weakness, and pontine infarction. Patient 3 was a 62-year-old Caucasian man with headaches, tremor, vertigo, and normal-pressure hydrocephalus. Patient 4 was a 50-year-old Caucasian man with radicular pain and peripheral facial palsy. Patients one, two, and three all had subnormal levels of CD4 cells, indicating impaired immunity. All patients were treated with oral doxycycline with good clinical outcome and normalization of CSF pleocytosis.

Conclusion

Given the low HIV-1 prevalence and medium incidence of Lyme neuroborreliosis in Western Sweden where these four cases were diagnosed, co-infection with HIV-1 and Borrelia is probably more common than previously thought. The three patients that were the most immunocompromised suffered from more severe and rather atypical neurological symptoms than are usually described among patients with Lyme neuroborreliosis. It is therefore important for doctors treating HIV patients to consider Lyme neuroborreliosis in a patient presenting with atypical neurological symptoms. All four patients were treated with oral doxycycline with a good outcome, further proving the efficacy of this regime.

Introduction

Lyme neuroborreliosis (LNB) is the most common bacterial central nervous system (CNS) infection in the temperate parts of the northern hemisphere. European LNB most often presents as a painful meningoradiculoneuritis, with or without facial palsy or other cranial neuritis (Garin-Bujadoux-Bannwarth syndrome). More uncommon symptoms include deficits of other cranial nerves, myelitis and encephalitis [1].
To date, only five single cases of co-infection with human immunodeficiency virus (HIV) -1 and LNB have been published [2-6], all of whom were treated with intravenous third-generation cephalosporins. In Sweden, the recommended treatment for LNB has long been oral doxycycline. We now present a case series of four patients with HIV-1 infection that have been diagnosed with LNB and successfully treated with oral doxycycline.

Case presentations

Patient 1

This 60-year-old Caucasian man had a medical history including intermittent alcohol problems and depression, for which he was treated with disulfiram and selective serotonin re-uptake inhibitors (SSRIs). He was diagnosed with HIV 23 years earlier but did not start antiretroviral therapy (ART) until 20 years after diagnosis (lamivudine, tenofovir and ritonavir-boosted atazanavir). Two years after commencing ART, he noticed a tick bite but no erythema migrans. One year later, he was admitted to hospital with confusion, psychomotor agitation and hyponatremia (serum sodium 116 mmol/L). He had completely stopped taking his HIV medication one month earlier, after a period of deteriorating compliance. The hyponatremia was thought to have been caused by a combination of water intoxication, syndrome of inappropriate antidiuretic hormone secretion and SSRI medication. It was corrected slowly and the patient improved with regard to confusion and agitation, but he showed remaining cognitive impairment. It was also noted that he had trouble walking and suffered from radicular pain in both legs. A computed tomography (CT) scan of his brain was normal. A cerebrospinal fluid (CSF) sample four weeks after admission showed markedly elevated levels of albumin and mononuclear cells (Table 1). High CSF and serum Borrelia antibody titers were present and the Borrelia antibody index was positive, indicating intrathecal antibody production. Treatment was given with 200 mg of oral doxycycline twice daily for 10 days. At the same time, ART was re-started. Three weeks later, his pain and motor symptoms had improved. The number of CSF mononuclear cells had decreased markedly (Figure 1). At follow-up six months later, this patient's symptoms had continued to improve and the level of mononuclear cells in his CSF was down to normal (data not shown).

CSF mononuclear cell count before and after treatment of Lyme neuroborreliosis with oral doxycycline. Each line represents one patient. Mean time between CSF samplings 47 days (30-70).

Patient 2

This 39-year-old Caucasian man had primary HIV infection six years earlier. Two years after that, he fell ill with Guillain-Barré syndrome, which was treated with intravenous gammaglobulin, and ART was started with stavudine, lamivudine, saquinavir and nelfinavir given for eight months. The Guillain-Barré symptoms resolved [7]. He was admitted with slowly increasing headaches, weakness in both legs and right hand tremor. On admission, he was still without ART and had a CD4 cell count of 390 cells/μL. Two days before admission, this patient had experienced a sudden onset of vertigo and hearing loss in his right ear. A magnetic resonance imaging scan showed a pontine infarction. Levels of albumin and mononuclear cells in his CSF were markedly elevated (Table 1). Borrelia-antibody titers were high in both his serum and CSF, and the Borrelia antibody index was positive. Treatment was given with 200 mg of oral doxycycline twice daily for 19 days. His symptoms of headaches, weakness, tremor and vertigo started improving within three days of starting treatment, but the hearing loss remained. Repeated lumbar punctures showed declining levels of CSF albumin (data not shown) and mononuclear cells (Figure 1). At follow-up after six months, he was still experiencing a complete hearing loss in his right ear, but the other symptoms had subsided. He still had no ART.

Patient 3

This 62-year-old Caucasian man was diagnosed with a primary HIV infection seven years earlier. Viral load was high and the CD4 cells were low at 180 cells/μL. ART was started with lamivudine, zidovudine and ritonavir-boosted lopinavir for one year and was re-started after four years with efavirenz, abacavir and lamivudine. One year later, the patient noted a change in the taste of coffee but no other foodstuff. In the following months, he experienced gradually increasing problems with vertigo and unsteadiness. A few months later, he also noted symptoms of tremor, urge incontinence and intermittent headaches. A CT scan revealed normal-pressure hydrocephalus. Six months later, CSF sampling showed increased levels of protein and mononuclear cells (Table 1). Culture and polymerase chain reaction tests for opportunistic infections were negative, but a cytological examination pointed to a neurotrophic infection. Four months after the first CSF analysis, a new analysis of CSF and serum revealed high titers of CSF and serum Borrelia antibodies and a positive antibody index, consistent with LNB. Treatment was given with 200 mg of oral doxycycline twice daily for 10 days. All the symptoms (including the change of taste of coffee) started improving within five days of treatment initiation. At follow-up two months later, the symptoms had almost completely disappeared and CSF levels of mononuclear cells and albumin had normalized (Figure 1).

Patient 4

This 50-year-old Caucasian man had been diagnosed with HIV five years previously. The date of infection was not known. He had been treated with ART for four years, initially lamivudine, zidovudine and ritonavir-boosted lopinavir, which were subsequently changed to efavirenz, emtricitabine and tenofovir. After treatment, his CD4 cell count had risen from 180 to 450 cells/μL. He fell ill with fever and headaches, plus a rash, which was later diagnosed as erythema migrans. Some days later he noted a right-sided facial palsy. His CSF levels of albumin and mononuclear cells were elevated (Table 1). Titers of Borrelia immunoglobulin M (IgM) antibodies in his serum and CSF were elevated, but IgG antibodies were not. Treatment was given with 100 mg of oral doxycycline twice daily for 21 days. The symptoms improved within a few days after treatment initiation. At follow-up two months later, the patient was still experiencing a slight sensibility disturbance from the right side of his face, but all the other symptoms had subsided and CSF pleocytosis and albumin concentration had normalized (Figure 1). Borrelia IgG antibodies in his serum and CSF were now positive.

Discussion

Only a few reports of HIV-1 and LNB co-infection have been presented. Previously, this was considered to be due to the non-overlapping epidemiology of the two diseases; with LNB mainly being a rural disease, while HIV-1 is more common in urban settings [5]. HIV-1 patients today who are treated with ART have a life expectancy approaching that of the general population and they seldom have opportunistic infections [8], thereby enabling them to lead active lives with outdoor activities that increase the risk of contracting Borrelia infection. The incidence of LNB is highest in Central Europe [9], where the prevalence of HIV-1 infection is also substantially higher than in Sweden, where these four patients were diagnosed. It can therefore be expected that HIV-1 and LNB co-infection is more common than has previously been described.
The diagnosis of LNB rests on a combination of clinical symptoms, CSF analyses and serology. The results are sometimes contradictory or difficult to interpret, making the diagnosis uncertain. In these four patients, however, the diagnosis of LNB is considered definite. At the time of diagnosis, all these patients had CSF mononuclear pleocytosis, with cell counts higher than the levels normally observed in HIV patients [10]. Patients 1, 2 and 3 all had high titers of IgG antibodies to Borrelia in their CSF and serum and a positive Borrelia antibody index, indicating the intrathecal production of specific Borrelia antibodies. Patient 4 seroconverted from negative to positive IgG antibodies to Borrelia in his serum and CSF. Furthermore, all the patients displayed a rapid response to anti-Borrelia treatment. There is a well-known cross-reactivity between the Borrelia spirochete and the Treponema spirochete and HIV patients are over-represented among patients with syphilis. However, screening tests for syphilis were negative in all four patients. Other bacterial, viral and fungal CNS infections were also ruled out.

Four of the five previously published cases of HIV-1 and LNB co-infection presented with typical symptoms of LNB, including bilateral facial palsy [5], headache [4], meningoradiculitis [3], and facial palsy and meningoradiculitis [2]. These four patients showed complete recovery on treatment with intravenous third-generation cephalosporins. The fifth patient presented with more severe symptoms consistent with encephalomyelitis: altered gait and difficulties in using her hands. Treatment with intravenous third-generation cephalosporins resulted in only partial recovery [6].

Three of the four patients described in this article presented with more severe, atypical symptoms and pathology than are usually seen in patients with LNB, including one with cognitive impairment, one with a pontine infarction and one with normal-pressure hydrocephalus. However, concomitant medical disorders such as alcohol abuse in Patient 1 and previous Guillain-Barré in Patient 2 might have influenced the clinical course of LNB. The atypical clinical picture might also have been caused by the long disease duration before Borrelia diagnosis and subsequent treatment; a couple of months for Patient 2, and more than a year for Patient 3. An explanation for the delayed diagnosis could be that more common HIV-associated opportunistic infections and other diseases were initially suspected. Apart from the concomitant medical disorders and the long disease duration, it must, however, also be suspected that these patients' impaired immunity contributed to the severity of the disease, as none of these three patients had normal levels of CD4 cells. The exact mechanisms by which impaired immunity in HIV infection might influence the course of disease in LNB remain to be clarified. Acute cerebral infarction is a known but very rare manifestation of LNB, with the pathological mechanism suspected to be a selective inflammatory process of small cerebral arteries. Patient 2 matches those previously described with the involvement of the posterior circulation and a generally favorable outcome after treatment [11]. Normal-pressure hydrocephalus in patients with LNB is an even rarer manifestation, with only a few known cases. The pathological background is not understood. As with Patient 3, previously described cases have also shown complete improvement after antibiotic treatment, with no need for ventricular shunting therapy [12].

The European Federation of Neurological Societies has published guidelines on the management of LNB [13]. According to these guidelines, patients with early LNB with CNS symptoms or patients with late (more than six months of symptoms) LNB should be treated with intravenous ceftriaxone. Of the four patients presented here, three had late LNB with CNS symptoms and were also the most immunocompromised. The good outcome of treatment with oral doxycycline in these patients, in combination with the CSF follow-up analyses, suggests that oral doxycycline is an excellent alternative to intravenous ceftriaxone in this patient group.

One interesting observation in Patients 1, 2 and 3 was the relatively higher HIV viral load in CSF compared with plasma at time of diagnosis of the Borrelia infection (Table 1). This shows that concomitant meningeal inflammation and the recruitment of lymphocytes to the CNS in HIV infection increase the CNS viral load, probably by the Trojan horse pathway [14]. Similar findings have been observed in patients with cryptococcal and tuberculous meningitis [15].

Conclusions

In this case series, we present four patients with HIV-1 and LNB co-infection diagnosed in Western Sweden, an area with a low HIV-1 prevalence and a medium incidence of LNB. Thus, co-infection with HIV-1 and LNB is probably more common than previously thought. The three patients that were the most immunocompromised suffered from more severe and atypical neurological symptoms than are usually described among patients with LNB. It is therefore important for doctors treating HIV patients to consider LNB if a patient presents with neurological symptoms. All four patients were treated with oral doxycycline with a good outcome further proving the efficacy of this regime.

Consent

Patient 1 had died at the time of writing of this article. Written informed consent was obtained for publication of this case series from the patient's brother. For Patients 2, 3 and 4 written informed consent was obtained. Copies of the written consents are available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

All the authors contributed to the design and data analysis of the study, the writing of the article and approved the final version.

Acknowledgements

This work was supported by the Faculty of Medicine, University of Gothenburg (project ALFGBG-11055).

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Sarcoidosis and Lyme Disease is a support network for people and friends of those with Sarcoidosis or Lyme Disease.

Sarcoidosis Australia was conceived by Sue Sherratt from a chance meeting with a couple of women in her doctor's waiting room towards the end of 2011, which carried on to a chat over coffee. The coffee must have been potent because it fueled Sue to go home and create an online support group for people with Sarcoidosis, Sue's own diagnosis.

One of the two women who shared Sue's coffee chat was diagnosed with Sarcoidosis and the other was looking more likely to have Lyme disease, so the group intended also to support Lyme disease patients. In one of those interesting quirks of fate, Sue was also found to have Lyme disease and the Lyme disease lady couldn't escape the possible-Sarcoidosis label. The confusion between Lyme disease and Sarcoidosis became a source of frustration and fascination at the same time. Hence, Sue's online support group decided to become an organisation and enter the fray to fight for all that was lacking in the medical system where Sarcoidosis and Lyme disease were concerned. Late in 2012, a committee was formed and in early 2013, the organisation became a charity.

Sarcoidosis Australia is in the process of changing name to Sarcoidosis Lyme Australia. Their mission is to support patients and carers, provide information to and educate patients/carers/medical clinicians/governments and to fund research.